The long-term goal of our research is to identify and/or develop novel therapeutics for the treatment of HAND. Here we proposed to study novel small chemical molecules that can inhibit GSK-3[unreadable], which is known to have important implications in HAND. These studies may help to identify mechanisms that play key roles in HIV-1 infection and provide a new set of preventive and/or therapeutic targets. In our preliminary studies, we have identified the GSK-3 inhibitor BIO, as a Tat-dependent HIV-1 transcriptional inhibitor out of 4,000 compounds screened. We have verified its ability to inhibit HIV-1 transcription in an independent assay system, TZM-bl cells, with an IC50 of 40 nM and a new BIO derivative (BIOder) at 4 nM in primary Macrophages and 0.5 nM in U87MG cells when infected with HIV-1. MTT toxicity assay shows an inhibitory activity of more than 10 uM in either primary cells or cell line. In an in vitro GSK-3[unreadable] kinase inhibition assay, we found that the drug has a very low IC50 of 0.03 nM. Finally we demonstrated that first generation BIO drug has neuroprotective effects on Tat induced cell death in rat mixed hippocampal cultures. Therefore BIO and its derivatives are unique compounds due to their dual mechanism of action with the ability to inhibit HIV-1 transcription as well as protect against Tat induced cell death. Based on these preliminary results we believe that BIO or its 2nd generation derivatives could be used as a therapeutic for HAND. The short term goal of our research is to determine if BIO is a potential HAND therapeutic. We hypothesize that BIO treatment is neuroprotective. The following specific aims address our hypothesis: Aim 1: Mechanism of BIO inhibition of HIV transcription. Aim 2: Effect of BIO on HIV induced neurotoxicity. PUBLIC HEALTH RELEVANCE: HIV infection can result in a number of neurological disorders including HIV-associated dementia, mild neurocognitive disorder, and asymptomatic neurocognitive impairment that are not prevented with HAART. Here we proposed to study novel small chemical molecules that can inhibit GSK-3b, which is known to have important implications in HAND, with the goal of abrogating Tat induced neuropathogenesis.